Asymmetric (4+3) cycloadditions of enantiomerically enriched epoxy enolsilanes

Article abstract of DOI:10.1002/anie.201207427

A f(oxy) allyl: The intermolecular (4+3) cycloaddition of enantiomerically enriched epoxy enolsilanes produces cycloadducts with up to 99 % ee, thus implying the reaction does not proceed by the putative achiral oxyallyl cation intermediate, but through a transiently chiral electrophile which retains the stereochemical information of the epoxide (see scheme; TES=triethylsilyl, Tf=trifluoromethanesulfonyl). Copyright

Full text of DOI:10.1002/anie.201207427

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Angewandte
Communications
DOI: 10.1002/anie.201207427
Synthetic Methods
Asymmetric (4+3) Cycloadditions of Enantiomerically Enriched
Epoxy Enolsilanes**
Brian Lo, Sarah Lam, Wing-Tak Wong, and Pauline Chiu*
The (4+3) cycloaddition reaction is a direct and efficient
method to construct seven-membered carbocycles.[1] Isoelec-
tronic with the Diels–Alder reaction, the classical mechanistic
understanding of this reaction is that an allyl cation dien-
ophile, contributing two electrons, undergoes cycloaddition
with the diene (Scheme 1). Cyclic dienes are commonly
Scheme 2. Diastereoselective (4+3) cycloadditions. TES=triethylsilyl,
Tf =trifluoromethanesulfonyl.
Scheme 1. Classical mechanism of the (4+3) cycloaddition. M=metal.
In contrast, for intermolecular (4+3) cycloadditions of
simpler enolsilanes such as the optically pure 5a (Scheme 3),
employed, thus resulting in bicyclic adducts which are useful
synthetic intermediates.[2] Compared with the (4+2) reaction,
however, asymmetric (4+3) cycloadditions remain under-
developed.[3] Other than two examples of asymmetric catal-
ysis,[4] the majority of asymmetric versions of (4+3) cyclo-
additions rely on chiral auxiliaries or incorporate chiral
elements into the reacting cation or the diene.[5,6]
the corresponding oxyallyl cation would be expected to be
On the basis of the seminal work by Eguchi et al.,[7] we
have developed a silyl-triflate-catalyzed intramolecular (4+3)
cycloaddition reaction of furan-tethered epoxy enolsilanes
such as 1, and it affords the cycloadduct 2 in excellent yield
and diastereoselectivity (Scheme 2).[8] The corresponding
intermolecular (4+3) cycloadditions with epoxy enolsilanes
such as 3a have also been observed to generate endo and
exo cycloadducts with facial selectivity (Scheme 2).[9] In both
cases, the reactions with optically active epoxy enolsilanes
generate cycloadducts with high conservation of the enantio-
meric excess.[8,10] Each of these cycloadducts has inherited one
stereocenter (* in Scheme 2) from the epoxide precursor, so
the observed selectivity could be understood as a diastereo-
selective cycloaddition of chiral oxyallyl cations, similar to the
previously reported asymmetric (4+3) cycloadditions involv-
ing chiral cations.[5]
Scheme 3. Asymmetric (4+3) cycloaddition of 5a.
devoid of any stereochemical elements, and should engender
racemic cycloadducts. However, we have observed that the
enantiomeric purity was, in fact, highly conserved in the
cycloaddition. The treatment of 5a, having a 99% ee, with
a catalytic amount of TESOTf in the presence of furan and
a subsequent Et3N·3HF desilylative workup resulted in endo
and exo diastereomers with 92 and 97% ee, respectively.[11]
Cycloaddition with the more reactive cyclopentadiene
afforded products with even higher enantiomeric excesses,
thus showing essentially a complete retention of chirality.
The absolute stereochemistry of the cycloadducts a-6a
and b-6a were determined by X-ray crystallographic analysis
of their (ꢀ)-camphanoyl and p-bromobenzoyl ester deriva-
tives, 7a and 7b, respectively (see the Supporting Information
for structures).[12] The observed absolute stereochemistry
implies that carbon–carbon bond formation occurred with
inversion of stereochemistry at the epoxide. The high degree
of enantiomeric excess observed in this (4+3) cycloaddition
shows that the reaction did not proceed through the putative
achiral oxyallyl cation intermediate, which would necessitate
that most, if not all, of the chiral information would be lost.[13]
We examined the generality of this phenomenon and the
scope of this reaction (Table 1). The epoxy enolsilane 5a
[*] B. Lo, S. Lam, Prof. W.-T. Wong, Prof. P. Chiu
Department of Chemistry, The University of Hong Kong
Pokfulam Road (Hong Kong)
E-mail: pchiu@hku.hk
[**] We thank Dr. S. K. Lam for first suggesting experiments using
optically pure epoxy enolsilanes. Support from the Research Grants
Council of Hong Kong (GRF HKU 7015/10P) and The University of
Hong Kong are gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207427.
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Table 2: Effect of the reaction conditions on the transfer of chirality.
underwent cycloaddition with a number of dienes with high to
very high degrees of transfer of chirality (Table 1, entries 1–
4), and the most reactive diene, cyclopentadiene, afforded the
Table 1: Scope of the asymmetric (4+3) cycloaddition.
Entry T [8C] Solvent
n
Yield [%][a]
d.r.[b]
ee [%][c]
(a-6a/b-6a) a-6a b-6a
1
ꢀ91 CH2Cl2
ꢀ91 CH2Cl2
ꢀ78 CH2Cl2
ꢀ40 CH2Cl2
ꢀ78 EtNO2
ꢀ40 EtNO2
ꢀ78 CH2Cl2
ꢀ78 CH2Cl2
ꢀ78 furan
5
5
5
5
5
5
1.5
75
68
62
51
58
51
15
69
67
54:46
55:45
54:46
55:45
53:47
56:44
54:46
51:49
40:60
92
89
90
83
71
60
89
92
93
97
97
96
90
85
76
94
96
97
2[d]
3
4
5
6
7
8
9
Entry
5
Diene
Yield [%][a]
d.r.[b]
(a-6/b-6)
ee [%][c]
Y
R2
a-6
b-6
30
>30
1
2
5a
5a
5a
5a
5b
5b
5c
5c
5d
O
CH2
O
(CH2)2C
O
CH2
O
H
H
Me
H
H
H
H
H
H
6a: 75
6b: 69
6c: 75
6d: 40
6a: 60
6b: 60
6a: 58
6b: 55
6b: 56
54:46
42:58
66:34
73:27
59:41
59:41
44:56
55:45
52:48
92
98
94
99
95
98
82
97
98
97
99
94
99
97
99
97
97
98
[a] Yield of isolated products. [b] Determined by 1H NMR spectroscopy .
[c] Determined by HPLC analysis using a chiral stationary phase.
[d] TfOH used instead of TESOTf.
3[d]
4[d]
5
6
7[d]
8
CH2
CH2
9
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy.
[c] Determined by HPLC analysis using a chiral stationary phase.
[d] 20mol% TESOTf used. TBDPS=tert-butyldiphenylsilyl, TBS=tert-
butyldimethylsilyl, TIPS=triisopropylsilyl.
Scheme 4. Possible electrophilic species in the (4+3) cycloaddition.
highest enantiomeric excesses. The nature of the silyl groups
on the enol ethers 5a–d did not have any significant effect on
the enantioselectivity of the reaction, and cycloadducts with
excellent ee values were uniformly obtained (Table 1,
entries 5–9).
which possesses planar chirality because of the triethylsiloxy
group which remains electrostatically associated with one
face of the activated species C1. The chiral C2 would
eventually undergo racemization to the dissociated, achiral
oxyallyl cation C3. This explanation is consistent with our
observations that increasing the temperature or polarity of
the medium, both of which favor dissociation, indeed resulted
in a diminished enantioselectivity in the reaction. The use of
a super-stoichiometric amount of the diene was found to
increase the ee value of the cycloadducts, presumably by
increasing the rate of reaction by intercepting either the chiral
species C1 or C2 before they racemize to C3.[15]
For epoxy enolsilanes where R ¼ H (Scheme 4), the
additional substituent should favor allyl cation formation,
and t1 should decrease. Stabilization of the cation should also
decrease the electrostatic interactions which maintain the
chirality in C2 and promote the formation of achiral C3,
therefore also decreasing t2. Hence we should expect to find
that when R ¼ H, the ee value of the cycloadducts would
decrease. The experiments in Table 3 sought to verify and to
examine the extent of the erosion of chirality transfer.
Indeed, the substituted epoxy enolsilanes 8a and 8b
underwent cycloaddition with greatly diminished enantiose-
lectivities in the range of 18–29% ee (Table 3, entries 1–3). As
previously observed, the enantioselectivity could be enhanced
by using a large excess of the cyclopentadiene (CpH), and was
recovered to 63–72% ee (Table 3, entries 3 and 4). Alterna-
tively, the ee value is also significantly improved to 59–64%
by using the same amount of diene, but conducting the
reaction in methylcyclohexane, a more nonpolar medium
We then investigated the effect of the reaction conditions
on the conservation of enantiomeric purity in this cyclo-
addition (Table 2). The use of either TESOTf or TfOH as
a catalyst to activate the epoxide resulted in enantioselective
reactions (Table 2, entries 1 and 2). Cycloadditions at ꢀ91 or
ꢀ788C afforded products with similarly high enantiomeric
excesses, but an additional increase in temperature resulted in
a decrease in the cycloaddition yield as well as the ee value
(Table 2, entries 3 and 4). The use of the more polar EtNO2 as
a reaction medium resulted in a 10–20% erosion in enantio-
selectivity (Table 2, entries 5 and 6). Increasing the amount of
the diene improves both the yield and the ee value of the
products (Table 2, entries 3, 7–9). Generally, the exo cycload-
ducts (b-6) were obtained with higher ee values than the
endo cycloadducts (a-6).
These results imply that a chiral electrophile is undergoing
reaction with the diene under these reaction conditions.[14]
The possibility of retaining the stereochemical integrity in the
oxyallyl cation precursor and utilizing it in the (4+3) cyclo-
addition has not been reported or exploited previously. At
this point, it is unclear which species along the continuum in
the evolution of the electrophile is being intercepted by the
diene to proceed to the cycloaddition (Scheme 4). It may be
an epoxy enolsilane activated by a Lewis acid (C1), a species
which then reacts with the diene in an SN2-like manner. The
electrophilic species could also be the oxyallyl cation C2,
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Table 3: (4+3) Cycloadditions of substituted epoxy enolsilanes 8.
Entry T [8C]
8
Solvent
n
Yield [%][a] d.r.[b]
ee [%][c]
(a/b)
a
b
1
2
3
4
5
6
ꢀ91
ꢀ91
ꢀ78
ꢀ78
ꢀ91
ꢀ78
8a CH2Cl2
8b CH2Cl2
8b CH2Cl2
8b CH2Cl2
8b MeCy
8b CpH
5
5
5
30
5
9a: 97
9b: 52
9b: 51
9b: 61
9b: 47
9b: 69
44:56 20 18
53:47 25 29
53:47 24 22
52:48 63 72
55:45 59 64
56:44 87 90
Scheme 5. Asymmetric synthesis of the DAT inhibitor 10. Reaction
conditions: a) TBDPSCl, imidazole, DMAP, CH2Cl2, 96%. b) SmI2,
iPrOH, MeCN, 87%, d.r. = 7:1. c) BzCl, pyridine, DMAP, CH2Cl2, 94%.
d) TBAF, AcOH, THF, 99%. e) CrO3/H5IO6, MeCN (containing H2O) ,
88%. f) MeI, K2CO3, acetone, 91%. g) H2, 10% Pd/C, MeOH, 98%.
Bz=benzoyl, DMAP=4-(dimethylamino)pyridine, TBAF=tetra-n-butyl-
ammonium fluoride, THF=tetrahydrofuran.
>30
[a] Yield of isolated products. [b] Determined by 1H NMR spectroscopy.
[c] Determined by HPLC analysis using a chiral stationary phase.
(Table 3, entries 2 and 5) in which the electrostatic associa-
tions are maximized and the lifetime of either C1 or C2 are
prolonged. Gratifyingly, by using cyclopentadiene as the
solvent, exploiting both the availability of the diene as well as
the effect of a nonpolar medium, the enantioselectivity was
largely restored from 22–24% to 87–90% ee (Table 3,
entries 3 and 6).
anticipated. The catalytic (4+3) cycloaddition with optically
pure epoxy enolsilanes affords cycloadducts with up to
99% ee under mild reaction conditions. Its utility has been
highlighted by an application to the asymmetric synthesis of
the DAT inhibitor 10 in high optical purity. Our ongoing
studies are probing the mechanism of this reaction by
experiment and computations, and using the optically pure
cycloadducts in various synthetic applications.
As a synthetic method, this reaction represents a unique
example of an asymmetric (4+3) cycloaddition in which the
chiral information of the epoxide has been directly translated
to the absolute stereochemistry in the cycloadduct, without
the need of any additional chiral elements or external chiral
catalysts. The cycloadducts are obtained as a pair of enantio-
merically enriched diastereomers, which can be valuable
chiral scaffolds for synthesis. To illustrate, the oxatropane 10
is a dopamine transporter (DAT) inhibitor designed by
Kozikowski et al. as a possible chemotherapeutic for cocaine
addiction.[16] The original synthesis relied on the desymmet-
rization of a meso oxabicyclic ketone by deprotonation using
a stoichiometric amount of a chiral lithium amide,[17] which
limited the enantiomeric purity of 10 thus obtained (ꢁ 85%
ee). However, using ent-b-6a, with a 97% ee from the
cycloaddition of ent-5a, in stereoselective manipulations as
shown in Scheme 5 ultimately yielded 10 in 53% overall yield
and with a greater than 99% ee.
Received: September 14, 2012
Published online: October 25, 2012
Keywords: allylic compounds · cycloaddition · heterocycles ·
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stereoselectivity · synthetic methods
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cation C2 (Scheme 4) are indistinguishable from products of
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ꢀ
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alkylation of the diene by the activated epoxide C1, which has
the formal outcome of a (4+3) cycloaddition.[18] The distin-
guishing characteristic would be whether the reactive inter-
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be delineated by computational chemistry. These results merit
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In summary, we have shown that there is a higher degree
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philic species undergoing (4+3) cycloaddition than previously
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[14] Chiral intermediates like C1 or C2 can also explain the
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[8] W. K. Chung, S. K. Lam, B. Lo, L. L. Liu, W.-T. Wong, P. Chiu, J.
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[11] Desilylation with TBAF results in racemization by converting
the less stable b-6a to ent-a-6a, and to a lesser extent, a-6a to
ent-b-6a.
[15] P. R. Carlier, D. C. Hsu, S. A. Bryson in Topics in Stereochem-
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[12] CCDC 6885848 (7a), 885846 (7b) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] In a cross-over experiment, a mixture of (ꢀ)-5a having a 99% ee
and (ꢂ)-8b reacted with CpH to generate 6b (97% ee) and 9b
(0% ee), respectively. In another cross-over experiment, a mix-
ture of (ꢂ)-5a and (ꢀ)-8b having a 99% ee reacted with CpH to
[18] Although some (4+3) cycloadditions have long been recognized
to be stepwise processes (Ref. [1a]), there has been less emphasis
to define what kind of electrophile is undergoing reaction.
[19] Recent computational and mechanistic studies: a) E. H.
Krenske, K. N. Houk, A. G. Lohse, J. E. Antoline, R. P. Hsung,
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